It was established decades ago that the principle estrogen of ovulating women is 17.beta.-estradiol. The desirability of achieving a physiologic level of 17.beta.-estradiol in estrogen replacement therapy is obvious. A substantial body of prior art has evolved over this period of time concerning the systemic administration of various estrogenic materials to treat estrogen deficiencies. The oral administration of 17.beta.-estradiol did not come into wide practice until it was made available in a micronized form which improved the solubility of estradiol thereby overcoming its poor gastrointestinal absorption. Micronized 17.beta.-estradiol has been given for estrogen replacement therapy by the oral route, cf: Martin, et al, Obstet. Gynecol., Vol. 39, page 771 (1972); and by the intravaginal route, either in the form of an aqueous suspension or solution, cf: Schiff, et al, Fert. Steril., 28/10, 1063-1066 (1977); and Rigg, et al, J. Clin. Endocr. Metab., 45/6, 1261-1264 (1977); or in a cream formulation, cf: Rigg, et al, New England J. Medicine, 298/4, 195-197 (1978); Dickerson, et al, Clin. Pharmacol. Ther., 26/4, 502-507 (1979); and Martin, et al, J. Amer. Med. Assoc., 242/24, 2699-2700 (1979). A vaginal cream formulation has some advantage over oral dosage forms for the replacement of 17.beta.-estradiol. Vaginal administration bypasses the ready gastrointestinal conversion of estradiol to estrone. Further, a vaginal cream preparation may be preferred due to other factors including: a different pharmacokinetic profile, patient convenience and comfort, and an added emollient effect of a cream formulation in the treatment of vaginitis, which is a common symptom of estrogen deficiency.
Stability testing of 17.beta.-estradiol vaginal cream formulations identical to those studied by Rigg, et al; Dickerson, et al; Martin, et al; supra. revealed a loss of estrogenic potency with time. This was an unexpected finding inasmuch as there is no teaching in the chemical art that 17.beta.-estradiol lacks stability. Indeed, shelf life studies with solid dosage formulations of estradiol have not revealed stability problems. In addition to loss of estrogenic potency with aging under storage conditions, there was also a deterioration of the physical properties of the cream formulation evidenced by graininess of texture. Therefore, the objectives of this invention were two-fold: to retard loss of estrogenic potency and to maintain physical stability of the cream formulation by devising an improved estradiol cream composition.